Mulzer, KÃ¶gl, Brecker and Warrass. ACIEE, 2007, EarlyView. DOI: 10.1002/anie.200703457.
A second Angewandte from the Mulzer lab in but a few weeks, this synthesis shares a little with the previous post on Platensimycin. Both natural products contain tightly functionalised polycyclic systems, and both are potent antibiotics. However Pasteurestin A&B are active against bovine illness, not human, so are humbled slightly in that respect. This synthetic work consists of the first synthesis and also confirmation of assignment, so lets get into the chemistry.
The chemistry really gets going with an auxiliary controlled Reformatsky addition, using an unsaturated aldehyde. This tin-mediated process gave them an interesting result, in that the stereochemistry of the hydroxyl was (S-), not (R-) as in the aldol with this system. They presumed that this must be due to the low temperature at which they ran the reaction, so they repeated it at RT, and found that the product rearranged before they could isolate it. I’m a little confused about the numbering of the atoms in their scheme, and no stereochemistry is given for the eventual product, so perhaps someone else can enlighten me…
A few simple synthetic transformations then gave them the SM for the awesome Vollhardt [2+2+2] cycloaddition, which went in moderate yield to give them three ring formations in one reaction. Acceptable efficiency, I feel. The next step was interesting too, but for different reasons… the selectivity here is impressive, and discussing this with my lab-mate, we reckon that is must be delivery of one electron to give the allyl anion, which is then protonated to give the most stable alkene. Thoughts?
The next few transformations are far more easily understood, and complete Pasteurestin B in a synthetically pleasing manner. Hydroboration of the remaining alkene and oxidation gave the ketone shown, which was selectively deprotonated, trapped with carbon dioxide and methylated to give the methyl ester. This was then deprotonated again, selentated and the selenide eliminated to give the desired enone.
Deprotection then gaveÂ Pasteurestin B in what was admittedly a rather linear route, but they were able to use a similar approach to get Pasteurestin A, showing the flexibility of the chemistry. Neat work.